Diabetes is one of the most serious health issues facing humanity with The World Health Organization reporting that approximately 346 million people worldwide have already been diagnosed with diabetes, making it a global challenge. Despite all of the new technologies and therapies diabetes remains the leading cause of blindness, amputations and kidney failure necessitating dialysis.
In the US alone, there are 23 million Americans with diabetes having a financial burden of $174 billion a year, which is as much as the costs of the conflicts in Iraq, Afghanistan and the global war on terrorism combined. Diabetes costs the US more than the $150 billion in damage caused by Hurricane Katrina. There are one million new cases of diabetes per year in the United States.
Current therapies for diabetes do no reverse the underlying mechanism of disease, which is a lack of beta cells that make insulin. Despite many well-intended lifestyle interventions and studies including the TODAY Study among children and adolescents diagnosed with diabetes, over time insulin is still required by most patients because at the time of diagnosis there is already a reduction in 90% and 50-75% of the beta cell mass in patients with type 1 and type 2 diabetes, respectively. None of the current therapies significantly increase beta cell mass.
Research carried out over the past century has more clearly found that generating new beta cells that make insulin is the key to reversing this disease. This invention specifically provides for novel methods and pharmaceutical compositions that have not been previously discussed or written about, other than by this inventor. The ability to transform extra-islet pancreatic tissue into new islets is a very new area of study.
The ability to transform ducts to islets is a new concept that is still questioned by many. For example, in mouse models, Melton and colleagues demonstrated that new beta cells arise only from existing beta cells and not from ductal progenitors in mice and this work has been central in the thinking among most in the field. Dor Y et al. 2004 Nature 429, 41-6.
In contrast, work by this inventor demonstrates clear and distinct differences between the islets of Langerhans in man and mouse and how new islets can and are formed from ductal progenitors in certain instances and by certain regenerative gene proteins and hormones in man but not in mice. Levetan C. 2010, J Diabetes; 2(2):76-84, Levetan C S, et al., Endocr Pract. 2008 December; 14(9):1075-83. Levetan C S and Pierce S M. Endocr Pract. 2012 Nov. 27:1-36. [Epub ahead of print]. The two clinical trials designed by this inventor utilizing an immune tolerance agent with a beta regeneration agent are the first described.
At present, the immunologists in the field of diabetes still maintain that given that diabetes is an autoimmune disease, sufficient and proper immune blockade should theoretically reverse diabetes since the mechanism of action of autoimmune destruction is blocked. This inventor contends that there is a major flaw to the current hypothesis that if immune destruction is blocked, then diabetes will be resolved.
Supporting this hypothesis that specifically posits that immune tolerance alone is not enough to reverse diabetes are human trials with immune tolerance agents given to new onset type 1 patients within the first months of diagnosis that have rendered 67.5% of patients insulin-free within 7 weeks. This efficacy can be sustained by 50% of patients after a year of therapy, but over time, all require insulin again. Bougneres P F. N Engl J. Med. 1988.17; 318(11):663-70, De Filippo G. Diabetes. 1996; 45(1):101-4. Unlike type 1 diabetes mouse models, humans have a much lower rate of beta cell turnover and immune tolerance alone in man does not provide regeneration of new beta cells to maintain insulin independence. At the time of diagnosis of type 1 diabetes, there is less than 10% of baseline beta mass remaining, and over time, without regeneration of new beta cells, there is continued apoptosis among the limited remaining beta cells.
This invention specifically provides new art that distinguishes the vast differences between the islets of Langerhans in men and mice, including the specific neuronal, vascular and cellular differences and differences in beta cell turnover rates. These differences account for why immune therapy successes in mice are not seen in men, and this invention addresses this lack of success by demonstrating that a beta regeneration agent is required with an immune tolerance agent to render humans with diabetes, insulin-free (Levetan C S Endocr Pract. 2012 Nov. 27:1-36. [Epub ahead of print]).
This inventor hypothesizes that the faster beta cell turnover rate in rodents compared to man may be due to the continuous eating patterns in rodents compared to man and also the greater percentage of beta cells compared to other cell types in rodents compared to man. This inventor explains that the success of reversing diabetes in rodents by treating NOD mice with an immune tolerance agent alone is not translated into humans because of the faster beta cell regeneration in rodents that is not seen in man. Thus, humans require both an immune tolerance agent and a beta regeneration agent for insulin independence.
Although combination therapy for type 1 diabetes has been discussed, the combination of an immune tolerance agent with a beta regeneration agent has not, nor has there been any mention of a proton pump inhibitor and an immune tolerance agent except by this inventor. For example, Matthews and colleagues recently published a paper entitled, “Developing Combination Immunotherapies for Type 1 Diabetes: Recommendations from the ITN-JDRF Type 1 Diabetes Combination Therapy Assessment Group,” which provides recommendations on reversing diabetes from frog thought leaders in the field of diabetes, with the conclusions that combination therapy consists of two immune tolerance agents without any mention of use of a beta regeneration agent. Matthews J B. Clin Exp Immunol. 2010 May; 160(2): 176-184.
According to Matthews and colleagues, “With these considerations in mind, the Assessment Group listed and prioritized combination therapies with the understanding that developments in preclinical (combination safety and efficacy) testing and/or ongoing clinical trials could subsequently affect the relative ranking. The Group indicated a preference for combination therapies with anti-CD3 and either antigen (such as oral insulin, GAD alum, proinsulin peptide or proinsulin DNA) or an IL-1 pathway anti-inflammatory (such as Anakinra or Rilonacept).” Table 1 from Mathews and colleagues lists two columns of immune tolerance agents to be placed in combination with one another with no mention whatsoever for the need of a beta regeneration agent, or any other agents for the treatment of type 1 diabetes other than immune modulation agents. Matthews J B, Clin Exp Immunol. 2010 May; 160(2): 176-184. The viewpoint that combination therapy for type 1 diabetes infers the use of two immune tolerance/immunomodulatory agents in combination with one another was also the conclusion of the 2012 City of Hope Annual Rachmiel Levine Diabetes Symposium. Additionally, none of the recommendations made by the Type 1 Diabetes Combination Therapy Assessment Group, Juvenile Diabetes Research Foundation International, Immune Tolerance Network mention the usage of generalized immune tolerance agents, such as cyclosporine, which this inventor finds to be the most effective immune tolerance agent for initial remission for recent onset diabetes. The Type 1 Diabetes Combination Therapy Assessment Group, Juvenile Diabetes Research Foundation International and the Immune Tolerance Network specifically only define cure as coming from targeted immune tolerance agents with no mention of cyclosporine, proton-pump inhibitors, beta regeneration agents, which are unique and specific to this invention. Matthews J B. Clin Exp Immunol. 2010 May; 160(2): 176-184.
There has been no mention by those proposing combination therapy of using an immune tolerance agent with a regeneration agent such as gastrin, proton pump inhibitors or Reg peptides. This invention describes new methods for reversing type I diabetes in human that specifically requires both an immune tolerance agent and a beta regeneration agent, which has not been discussed or studied or written about by previous investigators in the diabetes field.
One of the reasons that reversal of diabetes is only considered possible with immune tolerance agents is that diabetes is an autoimmune disease and so many immune agents have reversed diabetes in type 1 diabetes mouse models (NOD). This inventor disagrees with the conventional thinking described by Melton and others in mice, which claim that beta regeneration is only possible from other beta cells. This inventor has demonstrated that there are different pathways in man compared to rodents as well as the ability in man to transform extra-islet ductal tissue into new islets containing new pools of beta cells. Levetan C S. Endocr Pract. 2008 December; 14(9):1075-83, Levetan C. 2010, J Diabetes; 2(2):76-84, Levetan C S Endocr Pract. 2012 Nov. 27:1-36. [Epub ahead of print]). This invention provides methods for the treatment of diabetes wherein new islets can be formed from human ductal progenitors in the presence of a regeneration a agent such as proton pump inhibitors, which increase gastrin, resulting in the formation of new islets containing new pools of beta cells.
This inventor also shows why single therapy immune agents have been able to reverse diabetes in NOD models of type 1 diabetes in mice, but have not been able to reverse diabetes in man because a beta regeneration agent is specifically necessary in man due to the slower beta turnover rate in mice as compared to man. (Levetan C S Endocr Pract. 2012 Nov. 27:1-36. [Epub ahead of print]).
This inventor has also shown that in contrast to the many descriptions of similarities between the islets of mice and men of the past, human islets are vastly different from that of rodents in composition, architecture, innervation, and function. (Levetan C S Endocr Pract. 2012 Nov. 27:1-36. [Epub ahead of print]). Human beta cells are not clustered in the center of an islet as they are in rodents. Differing greatly from rodents, as much as 70% of human beta cells have direct physical associations with other endocrine cells (e.g., the alpha, delta, gamma/pancreatic polypeptide cells) and the greater percentage of non-beta cells in humans (Levetan C S Endocr Pract. 2012 Nov. 27:1-36. [Epub ahead of print]).
This inventor has furthermore described how human and non-human primate islets have more prominent and developed internal vasculature than rodents. Levetan C S Endocr Pract. 2012 Nov. 27:1-36. [Epub ahead of print]. The blood vessels within the human islet contain a larger proportion of smooth muscle cells, which has implications for the innervation of islets by the sympathetic nervous system fibers. Conversely, rodent islet vasculature consists mainly of endothelial tubes devoid of smooth muscle cells, and occupies a smaller physical space within the islets. Levetan C S Endocr Pract. 2012 Nov. 27:1-36. [Epub ahead of print]. Thus, sympathetic nerves may regulate the secretion of several hormones within human islets via the regulation of local blood flow, and play a greater role in human islets compared to rodents. Due to these differences, rodent models that have been successful using a sole immune tolerance agent may not apply to, and have been shown not to work in man for reversal of type 1 diabetes.
Although type 1 diabetes is an autoimmune disease, this inventor has demonstrated distinct differences and complexities in islets of humans as compared to rodents and why insulin independence requires more than a single or even multiple immune tolerance agent(s) to reverse the disease. Levetan C S Endocr Pract. 2012 Nov. 27:1-36. [Epub ahead of print].
Human islets differ in their cholinergic neuronal innervations in comparison to rodent islets, with additional evidence suggesting that there are more alpha cells than beta cells in man compared to the rodent because man is more dependent on glucagon regulation than mice. Levetan C S Endocr Pract. 2012 Nov. 27:1-36. [Epub ahead of print]. These findings are underscored in the 2012 review by Unger and Cherrington describing that the juxtaposition of the functioning beta cell is critical for the regulation of glucagon from the alpha cell, which is unique to man as compared to mice. Unger R H, Cherrington A D. J Clin Invest. 2012; 122:4-12. Man is much more dependent on other cell types than beta cells, and cannot regenerate all the cell types with an immune tolerance agent alone, as has been shown in rodents.
This inventor points out the striking differences in islet complexity of islets in man compared to mice and the importance of the alpha, delta, gamma and epsilon cells, which are present to a much smaller extent in mice, also suggesting the importance of paracrine communication and the presence of complex endocrine networks and neuronal feedback mechanisms (between the islets, the peripheral vasculature, and the central nervous system) that are necessary to narrowly maintain glycemic control in man. This islet complexity in man is not seen in rodent islets and is another reason why an immune tolerance agent alone is not enough to reverse diabetes.
This inventor specifically identifies that in humans, as compared to rodents, an immune tolerance agent(s) is/are not enough to sustain insulin independence, and specifically demonstrates, which is new to the art, that therapy with both an immune tolerance agent and a beta regeneration/islet neogenesis agent are required to sustain insulin-independence in man.
At present, islet neogenesis or beta regeneration agents have not been considered in the prior art because the concept of islet neogenesis and beta regeneration from ductal progenitors is very novel and does not fit in with the current convention that a disease like diabetes has an underlying autoimmune etiology. This inventor maintains that the past and present thinking that type 1 diabetes requires only targeted immunotherapy is incorrect, and new to the art is the concept that permanent diabetes remission requires both beta regeneration agents and autoimmune agents for insulin-independence.
The concept of using an immune tolerance agent with a regeneration agent is so new to the art because concepts of regeneration agents are new to the art and have not been considered by experts, yet, to be a possible therapy for diabetes. Prior art by this inventor has demonstrated the ability to transform human ducts to islets using Reg3a peptides, but this concept is still novel in the field of diabetes and has not yet been considered to have a role in diabetes reversal. (See U.S. Pat. Nos. 7,989,415, 7,393,919, 8,211,430, 7,714,103).
Supporting this hypothesis that a beta regeneration is required for reversal of diabetes in man, is data from twenty-five years ago by Bougneres and colleagues who reported in the New England Journal of Medicine that among forty children between the ages of 7 and 15 years of age with recent onset type 1 diabetes, 67.5% of patients were able to discontinue insulin within 48±5 days of initiation of 7.5 mg/kg/day of cyclosporine in two divided dosages. Bourgneres P F. N Engl J Med 1988; 318:663-670. By 12 months after the initiation of cyclosporine, 50% of patients remained insulin free. Over the next six years of follow-up, all of the initial cohort of patients required insulin. DiFillippo G. Diabetes 45:101-104, 1996. Over the first 4 years, the cyclosporine-treated group kept plasma C-peptide at levels twice as high as the control group (P<0.02) indicating that an immune tolerance agent plays a key role in diabetes reversal, but could not sustain the insulin-free state over time because there was no beta regeneration as indicated by the loss of C-peptide over time down to the levels of the insulin-requiring control group. After four years, there were no significant differences between the group treated with cyclosporine and the control group.
Other studies have found similar data that cyclosporine had a positive impact on recent onset type 1 diabetes patients, but over time, all patients required insulin. (The Canadian-European Randomized Control Trial Group. Diabetes 1988; 37:1574-82, Assan R. Diabetes Metab Res Rev 2002; 18:464-472, Feutren G. Lancet, 1986, 19; 2(8499):119-24).
The data on cyclosporine clearly demonstrate the efficacy of an immune tolerance agent for non-sustained remission of type 1 diabetes. However, the conclusion by the authors of the cyclosporin trials was that the risks outweighed the benefits for use of cyclosporine for type 1 diabetes due to lack of any sustained remission. This inventor disagrees with the convention of current expert panels in type 1 diabetes that have considered that cyclosporine no longer plays any role today or in the future for type 1 diabetes. Matthews J B. Clin Exp Immunol. 2010 May; 160(2): 176-184. Trials with cyclosporine fell out of favor because there were no permanent remissions over time. Additionally, over the past two decades, consensus groups including the Type 1 Diabetes Combination Therapy Assessment Group, Juvenile Diabetes Research Foundation and the International, Immune Tolerance Network, has specifically not mentioned any role for regeneration agents such as gastrin, PPI, or Reg peptides nor have these groups stated that there is any role for cyclosporine in type 1 diabetes.
Lack of permanent remission is hypothesized by this inventor as to why cyclosporine has been discarded as an appropriate agent for immune tolerance type 1 diabetes. Over the past two decades, many “targeted immune therapies” have been used for reversal of diabetes and shown to be successful in reversing diabetes in rodents, but have not proved successful in man. This inventor finds that none of the targeted immune agents have shown the success of cyclosporine. Despite the usage among recent onset type 1 diabetes patients, of more than twenty different immune agents over the past two decades utilized for protecting the remaining beta cells from further autoimmune attack, there has been not been the success seen in reversing diabetes as seen in rodents because there is no ability to sustain the remaining beta cells. It is estimated that fewer than 10% of functioning beta cells remain at the time of diagnosis of type 1 diabetes. This inventor specifically finds that a general immune therapy such as cyclosporine may be the preferred agent to targeted immune therapy because of the significant ability to render up to 67.5% of recent onset patients insulin-free, which has not been seen with any of the targeted immune therapy agents. Bourgneres P F. N Engl J Med 1988; 318:663-670).
Despite trials showing a positive impact of many autoimmune therapies initiated within twelve weeks of symptoms and diagnosis of type 1 diabetes, none have resulted in lasting insulin independence nor have any come close to the insulin-free rates of cyclosporine. Immune tolerance agents utilized among recent onset type 1 patients that have shown a potential immune benefit but have not resulted in significant or sustained insulin independence include, but are not limited to the heat shock protein 60, Diapep 277, Bacille Calmette-Guérin (also known as the BCG vaccine and commonly known as the vaccine against tuberculosis), mycophenolate mofetil, daclizumab, rituximab (anti CD20), anti CD3 antibodies including hOKT3 gamma1 (Ala-Ala), and the monoclonal antibody TRX4 (ChAglyCD3), CTLA4-Ig (abatacept) a selective co-stimulation modulator as it inhibits the co-stimulation of T cells, campath-1H, anti-CD52 antibody, a humanized monoclonal antibody to T-cells, polyclonal anti-T-lymphocyte globulin (ATG), GAD antibody vaccine based on the 65 kDa isoform of the recombinant human glutamic acid decarboxylase protein (rhGAD65), diazoxide and Alpha-1 Antitrypsin. This inventor specifically identifies cyclosporine as the best agent for initial remission for type 1 diabetes and methods of this invention demonstrate that the combination of cyclosporine and a proton-pump inhibitor (PPI) result in insulin independence among new onset and existing type 1 diabetes.
This invention contradicts the recent consensus panels (Type 1 Diabetes Combination Therapy Assessment Group, Juvenile Diabetes Research Foundation International, Immune Tolerance Network) recommendations that propose that diabetes can only be reversed with a combination of two targeted immune tolerance agents. Whereas, this invention specifically claims that the general immune tolerance agent cyclosporine is the best agent when combined with a PPI and/or other islet neogenesis agents for initial insulin independence among recent onset and existing type 1 diabetes. Because diabetes is considered an autoimmune disease, the diabetes community has yet to consider that combination therapy for reversal of type 1 diabetes could be defined as being a combination of an immune inhibitor and a beta regeneration agent.
New to the art is the potential reconsideration to use gastrin for new islet formation. Human trials conducted among type 1 patients reported promising results, although the results could not be sustained, likely due to lack of usage of an immunoprotective agent. Human clinical trials with gastrin and epidermal growth factor demonstrated reductions in daily insulin requirements by much as 75% within 3 months following four weeks of therapy among existing type 1 diabetes patients (Transition Therapeutics, Mar. 5, 2007). Lack of the ability to sustain these results was likely due to the ongoing autoimmune attack on the new beta cells generated by therapy.
Gastrin alone has been shown to induce beta cell neogenesis from human pancreatic ductal tissue without epidermal growth factor in in vitro studies (Suarez-Pinzon W L et al. JCEM. 2005; 90(6):3401-3409). Humans clinical trials with gastrin have not continued because the early success that was observed was not sustained, which this inventor posits was due to lack of an immune tolerance agent to protect the newly formed islets. Supporting this hypothesis is data by J J Meier and colleagues that demonstrates that the newest generated beta cells are the cells most vulnerable to autoimmune attack. Meier J J. Diabetologia 2006, 49: 83-89.
This inventor also disagrees with the current convention that proton pump inhibitors do not play a role in the diabetes armamentarium. This invention specifically provides methods for usage of proton pump inhibitors for insulin independence in type 1 and 2 diabetes and for usage in type 2 diabetes and PreDiabetes by the mechanism of action of increasing gastrin levels.
Among the gastrointestinal hormones demonstrated to result in new beta cell formation is gastrin, which was first described in the process of transforming human exocrine tissue to human endocrine tissue by Zollinger and Ellison in 1955. Zollinger R M and Ellison E H, Ann Surg. 1955; 142(4):709-28. Administration of gastrin has been shown both in rodents and humans to stimulate beta cell neogenesis and expansion of the beta cell mass in rodents. Suarez-Pinzon W L et al J Clin Endocrinol Metab 2005; 90:3401-3409, Rooman I, et al. Diabetes 2002; 51:686-690, Wang T C. J Clin Invest. 1993; 92(3):1349-56. A human clinical trial among patients type 1 diabetes using a combination of growth factors, including the direct usage of gastrin resulted in as much as a 75% reduction in insulin requirements at four weeks among type 1 diabetes patients.
Many other groups have also demonstrated the role of gastrin in increasing beta cell mass. For example, Rooman and colleagues found a doubling beta cell mass after infusion of gastrin in rats. Rooman I et al., Diabetes. 2002; 51(3):686-90. Other research teams have shown reversal of diabetes using gastrin with other growth factors including epidermal growth factor to expand the beta cell mass in rodent models. Yu H et al., Am J Med. Sci. 2011[Epub ahead of print], Suarez-Pinzon W L, Transplant Proc. 2008; 40(2):529-32, Suarez-Pinzon W L. Diabetes. 2005; 54(9):2596-601, Brand S J, Pharmacol Toxicol. 2002 December; 91(6):414-20.
Despite very promising data at 4 weeks utilizing gastrin in patients with type 1 diabetes, without the usage of an immune tolerance agent combined with any such agent that can increase beta regeneration, an improved impact on insulin requirements is not likely to be sustained. Data from J J Meier and colleagues demonstrates that the newest beta cells are the ones that are most vulnerable to cytokine-induced death and trigger autoimmune attack. Meier J J et al Diabetologia 2006; 49(1):83-9.
Despite early findings of patients with type 1 diabetes demonstrating a significant reduction in insulin requirements and improvements in hemoglobin A1C in just four weeks, sustained results have not been seen and clinical trials have been abandoned. This inventor hypothesizes that without an immune tolerance agent to protect newly formed beta cells, autoimmune destruction limits any ability for sustained insulin independence. Similar to the great success seen among many immune tolerance agents utilized among recent onset type 1 patients, without new beta cell formation over time, the limited amount (fewer than 10%) of beta cells remaining at the time of type 1 diagnosis will undergo apoptosis until patients require insulin again. Clinical trials using gastrin alone have been terminated due to lack of sustained efficacy among patients with existing type 1 diabetes. Thus, it is critical to have an immune agent on board at the time that new beta cells are being generated.
Proton pump inhibitors (PPIs), in addition to their primary usage for reducing gastric acid, also secondarily increase gastrin. Studies conducted among patients on a high-range dosage of the PPI Lansoprazole (90 mg/day) for 6 years or greater resulted in a sustained safety profile and gastrin levels that were nearly 7-fold higher than normal. Cadiot G et al., Gastroenterol Clin Biol. 1995; 19(10):811-7. The range of normal gastrin values may vary from lab to lab with normal values that may be higher in very young children and older adults, but are generally <100 pg/mL.
Hove and colleagues in a randomized prospective clinical trial among patients with type 2 diabetes utilizing the proton pump inhibitor esomeprazole concluded that “Treatment with esomeprazole over 12 weeks did not improve insulin secretion, glycaemic control or cardiovascular disease biomarkers in patients with type 2 diabetes.” Hove K D, Brøns C, Færch K, et al., Diabetologia. 2013 January; 56(1):22-30. This inventor came to a different conclusion in reviewing the data and concluded that proton pump inhibitors may play an important role in preservation of endogenous insulin secretion. Based on this inventor's conclusion, which varied markedly from that of the authors, this inventor wrote a letter to the editor of Diabetologia with a colleague stating the following:
“In the January issue of this journal Hove et al. reported that treatment with 40 mg esomeprazole over 12 weeks in patients with type 2 diabetes did not improve insulin secretion, glycaemic control or change the biomarkers of cardiovascular disease. Hove K D, Brøns C, Færch K, et al. 2013. Diabetologia 56:22-30. Here we offer a different viewpoint on the data presented by Hove et al. These authors help elucidate whether proton pump inhibitors may play a role in the diabetes armamentarium by raising gastrin levels. Gastrin was initially shown to have the potential to increase new beta cell formation by Zollinger and Ellison in 1955. Zollinger R M, Ellison (1955). E H. Ann Surg. 142:709-23.”
“Hove and colleagues report a 9-fold increase in the area under the curve (AUC) of gastrin among 20 type 2 diabetes patients treated with esomeprazole, whereas patients on placebo had no significant rise in gastrin. However, based on the metabolic outcome the authors concluded that treatment with esomeprazole over 12 weeks did not improve insulin secretion or glycaemic control. We have looked at the data and found that patients in the control group had a significant 16.3% reduction (p=0.002) in AUC, whereas the esomeprazole treated patients had no decline in insulin AUC. Given the natural history of 2 diabetes characterized by the progressive loss of insulin secretion, its maintenance utilizing a proton pump inhibitor may demonstrate the potential role for such agent in the course of the disease to preserve or enhance beta cell regeneration. In this respect the effect of proton pump inhibitors might be also of interest in type 1 diabetes. Thus, previous studies utilizing gastrin and epidermal growth factor among type 1 diabetes patients found that the greatest impact was seen 1-3 months post-treatment. (Transition Therapeutics, Mar. 5, 2007)
“We believe that these results are encouraging and that further studies should be carried out to demonstrate the potential of proton pump inhibitors to preserve beta cell function. Studies among recently diagnosed type 1 diabetes patients using a proton pump inhibitor accompanied by an immune tolerance agent, could be an attractive option.”
This inventor specifically identifies and defines that proton pump inhibitors may play an important role in beta regeneration by increasing gastrin levels and may therefore be utilized among both type 1 and type 2 diabetes for both preservation and regeneration of beta cells. This hypothesis is supported both by the findings of Zollinger and Ellison in 1955, which specifically demonstrate the formation of new islets by gastrin. Zollinger R M, Ellison (1955). E H. Ann Surg. 142:709-23.
This inventor also claims that PPIs can successfully be used not only in type 1 diabetes, but in type 2 diabetes. Type 2 diabetes results from a different etiology, but similar to type 1 diabetes there is a substantial loss of 50-75% of beta cell mass at the time of diagnosis; however, the loss is not as acute as that seen from the autoimmune destruction in type 1 diabetes. The beta cell loss seen in type 2 diabetes is due to a more chronic beta cell loss that is impacted by a number of factors including lifestyle, free fatty acids and genetics. Thus, while the beta call loss is not due to sudden autoimmune destruction as in type 1 diabetes, there is still the need for beta cell regeneration and sustained beta cell mass.
Among type 2 diabetes patients, there is a gradual 50-80% reduction in beta cell mass by the time of diagnosis compared to a more acute reduction in beta mass by 90% or more among type 1 patients, who commonly have an autoimmune component to their beta cell loss. Although the beta cell mass may expand several fold from birth to adulthood, this is not enough to compensate for the greater rate of beta cell loss than generation than occurs in both type 1 and 2 diabetes.
Two recent NIH studies, one in children and adolescents and the other in adults demonstrate that intensive lifestyle interventions designed to improve and impact type 2 diabetes simply have no effect in children and adolescents in glycemic control and do not limit the need for patients to move on to insulin therapy for better control of their diabetes. The TODAY Study Group. N Engl J. Med. 2012 Apr. 29. [Epub ahead of print]. Diabetes Research Program Prevention Group, Lancet. 2009; 374(9702): 1677-1686. Among children and adolescents with type 2 diabetes, therapy with metformin or lifestyle interventions did not improve diabetes control or the necessity for insulin therapy.
The TODAY study illustrates the need for new insulin-secreting beta cells to delay or prevent the adverse vascular complications of diabetes. Despite the many new treatments and technological armamentariums for diabetes, diabetes-related complications including retinopathy, blindness, neuropathy, amputations, renal insufficiency and dialysis, along with macrovascular complications including heart attack, stroke and peripheral vascular disease, continue to rise among patients with diabetes. For example, recent studies among patients with type 1 utilizing the newest technological advances including the use of glucose sensors that are located within the insulin pump that measure 288 glucose levels per day have not improved hemoglobin A1C levels as much as those seen in the DCCT trial conducted more two decades ago when sensor technology was not available and shorter acting insulin analogs were also not on the market. The DCCT Research Group. N Engl J. Med. 1993; 329(14):977-986, Bergenstal R M et al, N Engl J Med, 2010; 363(4):311-320. Bergenstal R M, et al, Diabetes Care. 2011; 34(11):2403-2405.
There is a dire need to restore new beta cells and maintain beta cell mass among type 1 and type 2 diabetes. The loss of endogenous insulin is directly correlated with a multiplicity of atherogenic risk factors for microvascular and macrovascular complications. Lack of insulin, which is the hallmark of diabetes results not only in elevated glucose levels, but also results in a large number and wide complexity of metabolic abnormalities. For example, lack of insulin results in diminished activation of lipoprotein lipase resulting in increased levels of triglyceride-rich lipoproteins including chylomicrons and very low-density lipoproteins.
The field of beta regeneration is in its infancy and the concept of a beta regeneration is still very new. This inventor has previously shown that the human Reg gene peptides are directly involved in new beta cell formation from extra-islet ductal tissue. Gastrin has also been shown to generate new islets from ductal tissue. Others have confirmed the presence of Reg in the pancreas of newly diagnosed human diabetes, with subsequent data in both human ductal tissues and from BrdU studies showing that Reg serves to directly form new beta cells from extra-islet ductal tissue, as is the case with gastrin. Levetan C S et al, Endocr Pract. 2008; 14(9):1075-1083, Rosenberg L et al, Diabetologia. 1996; 39:256-262, Li J et al, Peptides. 2009; 30(12):2242-2249, Dungan K M et al, Diabetes Metab Res Rev. 2009; 25(6):558-565. Zollinger R M, Ellison. E H. Ann Surg. 1955 October; 142(4):709-23, Wang T C, Bonner-Weir S, Oates P S et al., J Clin Invest. 1993 September; 92(3):1349-56, Wang R N, Rehfeld J F, Nielsen F C, et al., Diabetologia. 1997 August; 40(8):887-93.
Previously, this inventor demonstrated that a human Reg3a gene protein has successfully been administered to human pancreatic ductal tissue devoid of islets resulting in a significant increase in insulin concentrations indicating new beta cell formation; a 3-fold rise in total beta cells staining insulin in STZ-rendered diabetic mice was observed. Levetan C S., et al, Endocr Pract. 2008; 14(9):1075-1083. Reg3a protein and placebo-treated mice underwent an overnight fast and a fasting glucose level on the morning of day 39 of treatment. Fasting glucose levels were 258.00±84.5 mg/dl in the placebo group compared to a fasting glucose level of 111.00±11.4 mg/dL (P=0.020) in the Reg3a protein-treated mice.
To date, there has been limited awareness or acknowledgement of the Reg peptides in the diabetes community. As there are no Reg peptides on the market, this invention provides a specific and completely novel approach to the art by using a proton pump inhibitor for insulin independence, which increases gastrin levels up to 9-fold in man, along with an immune tolerance agent to protect newly formed beta cells. Hove K D, Brøns C, Færch K, et al., Diabetologia. 2013 January; 56(1):22-30.
This inventor has also investigated the role and pathways of other human hormones involved in beta cell regeneration with findings consistent with initial findings of Moore and colleagues in 1906, demonstrating the role of gastrointestinal hormones in improving diabetes control among three patients with type 1 diabetes. Levetan C. 2010, J Diabetes; 2(2):76-84, Moore et al, Biochem J. 1906; 1(1): 28-38. The mechanism of action of these gastrointestinal hormones were not only found to be in insulin secretion, but decades later these gut peptides have been shown to be involved in the transformation of extra-islet exocrine tissue into new endocrine tissue containing beta cells. Wang T C. J Clin Invest. 1993; 92(3):1349-56.
Not until 1999, when the use of cell lineage labeling became available, did the embryological concepts of the pancreas change. Whereas it had been thought that the pancreas was derived from both ectoderm and endoderm, it has now been shown that the entire pancreas arises only from endoderm during embryological development. This helps explain how beta progenitor cells have been described as residing diffusely throughout the adult pancreatic tissue and how growth factors transform pancreatic extra-islet ductal tissue into new beta cells. Over the past several decades, the ability to regenerate new beta cells from progenitor cells found within the pancreatic ductal tissue has been illustrated by many teams.
This invention provides new methods to the art of the combination of gastrin or usage of a PPI with an immune tolerance agent. The clinical trials set forth by this inventor are completely new to the art in the approach of using a beta regeneration agent with an immune tolerance agent, as well as using a general immune tolerance, cyclosporine, which has not been considered as possible therapy for diabetes for decades.
The immunosuppressive drug cyclosporine has been shown to have long-term safety and short-term efficacy for rendering new onset patients with type 1 diabetes insulin-independent. The immunosuppressive effects of cyclosporine were discovered in 1972 in a screening test on immune suppression designed and implemented by Dr. Hartmann Stähelin. The success of cyclosporine in preventing organ rejection was later shown in kidney transplants by Calne and colleagues at the University of Cambridge and in liver transplants performed initially at the University of Pittsburgh Hospital. Cyclosporine was subsequently approved for use in 1983. Since then, it has been used to prevent and treat graft-versus-host reactions in bone marrow transplantation and to prevent rejection of kidney, heart, and liver transplantation.
In addition to transplants, cyclosporine has also been used in psoriasis, severe atopic dermatitis, pyoderma gangrenosum, chronic autoimmune urticaria, and, infrequently, in rheumatoid arthritis and related diseases. It is commonly prescribed in the US as an ophthalmic emulsion for the treatment of dry eyes. Cyclosporine has also been used to help treat patients with acute severe ulcerative colitis that do not respond to treatment with steroids. This drug is also used as a treatment of posterior or intermediate uveitis with noninfective etiology. Cyclosporine is also currently used to experimentally treat cardiac hypertrophy.
To date, there have been no studies that combine an immune tolerance agent with a known beta cell regeneration growth factor that has been shown to directly stimulate the formation of new beta cells from ductal cells. The prior art in the field has described the usage of gastrin with other growth factors, but has never specifically used an immune tolerance agent in combination with these agents (See U.S. Pat. No. 6,992,060), When gastrin itself is given to type 1 patients without an agent to prevent autoimmune destruction of new beta cells, there has only been improvement over a 4-week period due to autoimmune destruction.
One of the reasons that this combination of an immune tolerance agent with gastrin or a PPI has not previously been considered and has not been obvious is because dozens of preclinical trials with rodent type 1 diabetes models including NOD mouse models have shown only the need for gastrin and other beta cell growth factors for reversal of diabetes. Likewise, rodent type 1 diabetes models including NOD mouse models have shown that using a immune tolerance agents alone is all that is needed to reverse type 1 diabetes in mice.
This inventor has shown great distinctions between the insulin-producing islets of mice and men with humans having much more complex islet structures with respect to composition of cell type, neural and vascular innervation and unique paracrine interactions that are not found in rodents. Levetan has demonstrated vast differences in the islets of mice and men, which may explain the many, many studies conducted among rodent models in the field of diabetes that later are unable to be replicated in human studies. Levetan C S et al. Endocr Pract. 2012; 27:1-36. [Epub ahead of print]. Specifically, trials with multiple different agents and types of agents have been utilized in preclinical rodent models evaluating agents that may be successful in clinical practice for usage in patients with type 1 diabetes. This inventor has also previously shown, like many other scientific teams, that after fetal development of beta cells, typically new beta cells are only derived from the existing, surviving beta cell population. Different and unique to the previous art in the field, this inventor has shown the ability to postnatally generate new beta cells by the transformation of human pancreatic ductal tissue. Levetan C. J. Diabetes. 2010; 2(2):76-84, Levetan C S. Endocr Pract. 2008; 14(9):1075-83.
New and unique research by this inventor, which has not been obvious in the prior art, is 1) the ability to reverse diabetes in the diabetic mouse models may be flawed by the complexity of the human islet compared to that of the rodent and 2) the process of generating new beta cells must be from a different source than from the beta cells remaining after the diagnosis of type 1 or type 2 diabetes is made because of the limited supply (<10% for type 1 diabetes and <50-75% for type 2 diabetes). This inventor has shown the ability to transform new pools of beta cells within new islets from extra-islet ductal tissue (See U.S. Pat. Nos. 8,211,430, 7,989,415, 7,714,103 and 7,393,919).
There is a need in the art for new therapeutic modalities for the treatment of diabetes in humans that generate new beta cells from extra-islet tissue while preserving the population of nascent beta cells from destruction by the immune system.